tbuckley/cabot-search huggingface dataset:
MDB-41. TARGETING EPIGENETIC REGULATORS TO INHIBIT GROUP 3 MEDULLOBLASTOMA MIGRATION
Authors: Nitish Jangde, Thomas Jordan Walter, Nagi Ayad
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma highly malignant type of childhood brain cancer which develops at the cerebellum. Medulloblastoma can be grouped into four molecular subtypes; Sonic Hedgehog (Shh), Wnt, group 3, and group 4 based on their molecular development. Mostly group 3 medulloblastoma are highly malignant subtype. Medulloblastoma migration from the cerebellum to the leptomeningeal space and spinal cord is critical for worsening the symptoms. Targeting the medulloblastoma migration would potentially attenuate the symptoms. Identifying potential epigenetic regulators and targeting them might be an effective approach to cure the symptoms in medulloblastoma patients. CRISPR epigenome library screening targeting more than 500 epigenetic factors by using more than 3000 sgRNA can help to identify potential epigenetic regulators to medulloblastoma migration. Group 3 medulloblastoma tumor is highly malignant so, we have selected a group 3 medulloblastoma human cell line D425 for our study. CRISPR epigenome library or sg RNA targeting 500 epigenetic genes was introduced into D425 cells with the help of lentiviral particles. The cells were antibiotically selected and expanded after selection. In vitro, trans-well migration assays were performed with technical and biological replicates. The cells that migrated through the transmembrane were collected and the cells which did not show any migration were also collected followed by enrichment. The DNA isolation followed by amplification of barcoded sequences identifiers tagged to different sgRNAs were size selected and undergone for Illumina NGS sequencing. The NGS sequencing results will reveal the key epigenetic factors involved in the migration of Group 3 medulloblastoma. After confirmation of pathway analysis and in vitro and in vivo validation would identify potential factors. This study will ultimately help us to find a potential epigenetic regulator for targeted therapy to inhibit migration of group 3 medulloblastoma to reduce the symptoms and combine with other effective drugs to establish synergistic effects for treatment.
How Would You Manage This Patient With Recurrent Diverticulitis?
Authors: Howard Libman, Judy W. Nee, Anthony J. Lembo, Risa B. Burns
Journal: Annals of Internal Medicine (2023)

Acute diverticulitis, which refers to inflammation or infection, or both, of a colonic diverticulum, is a common medical condition that may occur repeatedly in some persons. It most often manifests with left-sided abdominal pain, which may be associated with low-grade fever and other gastrointestinal symptoms. Complications may include abscess, fistula formation, perforation, and bowel obstruction. The American College of Physicians recently published practice guidelines on the diagnosis and management of acute diverticulitis, the role of colonoscopy after resolution, and interventions to prevent recurrence of this condition. Among the recommendations were the use of abdominal computed tomography (CT) scanning in cases where there was diagnostic uncertainty, initial management of uncomplicated cases in the outpatient setting without antibiotics, referral for colonoscopy after an initial episode if not performed recently, and discussion of elective surgery to prevent recurrent disease in patients with complicated diverticulitis or frequent episodes of uncomplicated disease. Here, 2 gastroenterologists with expertise in acute diverticulitis debate CT scanning for diagnosis, antibiotics for treatment, colonoscopy to screen for underlying malignancy, and elective surgery to prevent recurrent disease.
MDB-01. ELUCIDATING THE ROLE OF THE BAIAP2-CDC42 INTERACTION MEDULLOBLASTOMA
Authors: Luz Ruiz, Rober Suter, Nitish Jangde, Nagi Ayad
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Despite advancements in treatment, there is still no significant improvement in survival rates. This indicates novel, more effective treatment options are necessary. In addition, when medulloblastoma is metastasized outside the central nervous system, there is worst mortality rate. The regulatory properties of metastasis and invasion are still not well understood. We sought to identify potential key regulators for these processes in medulloblastoma. Single-cell RNA sequencing data was collected for medulloblastoma patients and an experiment with a Tg (Neurod-Smoothened*A1) mouse. We identified BAIAP2 and CDC42 to be differentially expressed compared to non-tumor brain cells. Previous literature shows that these genes are implicated in oncogenic properties including invasion, migration, and proliferation in different cancers and neurological diseases. We hypothesize that distinct cell populations within medulloblastoma should show different expressions of BAIAP2 and CDC42, specifically those involved in invasion and migration. We determined that BAIAP2 and CDC42 have higher expression in medulloblastoma tumors compared to the control. In our data, the cell population enriched for microtubule depolymerization had a high expression of BAIAP2, unlike the other clusters. This study is important because BAIAP2 and CDC42 have yet to be characterized in medulloblastoma. Our data suggest a potential role for BAIAP2 and CDC42 in the pathophysiology of medulloblastoma which can possibly be a target for future studies.
LGG-05. IMAGING-BASED DEEP LEARNING FOR EVENT-FREE SURVIVAL PREDICTION IN PATIENTS WITH PEDIATRIC LOW-GRADE GLIOMA
Authors: Anna Zapaishchykova, Hasaan Hayat, Zezhong Ye, Sridhar Vajapeyam, Rishi Balraj Chopra, Aidan Boyd, Kevin X Liu, Hugo J W L Aerts, Pratiti Bandopadhayay, Daphne A Haas-Kogan, Ali Nabavidazeh, Adam C Resnick, Sabine Mueller, Tina Y Poussaint, Tabitha M Cooney, Benjamin H Kann
Journal: Neuro-Oncology (2023)

Abstract Pediatric low-grade gliomas (pLGGs) have heterogeneous outcomes, making individualized clinical decision-making challenging. Imaging-based biomarkers for progression and/or recurrence may better risk-stratify pLGG patients and guide management. We developed and externally validated a deep learning (DL) algorithm to predict event-free survival (EFS) in pLGG using multi-institutional databases. We collected linked, T2-weighted diagnostic Magnetic Resonance Images (MRI) and clinical data for patients with WHO grade 1-2 pLGG (diagnosed from 1991-2017) from the Children’s Brain Tumor Network (CBTN, n=176, median follow-up: 3.7 years, IQR=2-6.8 years) for model development and internal validation, and Boston Children’s Hospital (BCH, n=219, median follow-up: 8.8 years, IQR=4-13.4 years) for external validation. Leveraging a self-supervised learning approach, we trained a DL Unet model for tumor segmentation and used it for extracting image features. We combined 12 DL-imaging features with three clinical variables (age, sex, and surgical resection status (gross total/subtotal/no resection) and trained a Deep Cox Mixtures(DCM) model for survival analysis. We externally validated the performance of three models: clinical, DL-imaging, and combined DL-imaging and clinical. The combined DL-imaging and clinical model outperformed the clinical alone and DL-imaging alone models for prediction of 3-year EFS (time-dependent AUC: 0.85, 0.73, 0.53, respectively) with improved calibration (Integrated Brier Score: 0.08, 0.13, 0.15, respectively). Using the combined DL-imaging and clinical model output, patients were divided into low and high-risk groups based on mean event probability (3-year EFS 53% vs 86%, p=0.02). Variables associated with poor EFS were imaging score, lower age, and lack of gross total resection. In conclusion, deep learning-derived, MRI-based imaging features may improve prediction of event-free survival and risk stratification for patients with pLGG.
LGG-22. CHARACTERIZATION OF THE TUMOR MICROENVIRONMENT IN PEDIATRIC LOW-GRADE GLIOMA
Authors: Shadi Zahedi, Kent Riemondy, Andrea Griesinger, Andrew Donson, Rui Fu, Michelle Crespo, Madeline Groat, Emil Bratbak, John Desisto, John Rheaume, Adam Green, Rajeev Vibhakar, Nicholas Willard, Nicholas Forman, Jean Mulcahy Levy
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) are the most common brain tumors in children. Although pLGGs represent a significant number of patients with slow-growing, often curable tumors, they are also affected by neurologic injuries, multiple relapses and requiring repeated courses of therapy, including surgery, chemotherapy, and radiotherapy. Novel, more effective therapies are urgently needed. METHODS We used a multipronged approach to better understand the complexity of the tumor microenvironment (TME) within pLGG. We utilized scRNA sequencing, spatial transcriptomics, and cytokine analyses on 23 patient-derived pLGG samples including different tumor types (pilocytic astrocytoma (PA), ganglioglioma (GG), and undefined low-grade glioma (LGG)) and mutation profiles (BRAF V600E, BRAF fusions, and BRAF wild-type) to identify cell types, their spatial arrangement within a tissue, and their underlying functional status. RESULTS scRNA seq revealed both tumor and immune cells within the TME. Analyses of tumor cell subsets revealed a developmental hierarchy identifying progenitor and mature cell populations. Immune cells comprised both myeloid and T lineage cells, with myeloid cells comprising &amp;gt; 50% of the entire population. Interestingly, there was a significant difference between the prevalence of two major myeloid subclusters between two pLGG subtypes (PA and GG). To better understand the underlying difference, we performed bulk and single-cell cytokine analyses to identify immune signals via which these cells communicate. Cytokine analyses revealed distinct immune phenotypes among tumor samples. Notably, BRAF fusion tumors appeared more immunogenic, especially by secreting higher levels of immune cell activators, chemokines (including CCL3 and CCL4), compared to BRAF V600E tumors. Additionally, spatial transcriptomics revealed the differential expression of these chemokines between PA and GG tumors. CONCLUSIONS Characterization of pLGG demonstrated the complexity of tumor microenvironment among different pLGG subtypes. Further investigation of the immune cells and tumor-immune cell interactions has the potential to unravel novel therapeutic targets against pLGG.
IMMU-22. ALLOGENEIC NK CELLS SECRETING IL15 AND RESISTANT TO TGF-β Show Antitumor Activity Against Gliobastoma
Authors: Nethaji Muniraj, Kajal Chaudhry, Joshua Terao, Luke Barron, Vipin Suri, Catherine Bollard, Conrad Russell Cruz
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION High grade brain cancers, like most solid tumors, often relapse and are resistant to current therapies. Limited efficacy to cell therapy may be related to intratumoral heterogeneity and the suppressive tumor microenvironment. Hence, we aimed to modify allogeneic natural killer (NK) cells, which can recognize expressed tumor stress ligands, to resist TGF-β and secrete IL15. METHODS Cord blood-derived NK cells were expanded and modified to express IL15 and a dominant negative receptor (DNR) against TGF-β. NK cell product activity against the GBM cell line U87MG were evaluated in vitro and in vivo. The behavior of these cells were also analyzed ex vivo, to evaluate the impact (including potential toxicity) of increasing the potency of this allogeneic NK cell product. RESULTS While animals injected with NK cells secreting IL15 and expressing DNR successfully cleared tumors 6 days after T cell infusion, we did not observe significant differences in survival between the groups (no treatment control mice vs treated with mock-transduced NK cell vs DNR-transduced NK cells vs IL-15/DNR-transduced NK cells). Therefore, we sought to determine whether cytokine-related toxicity was responsible for death in the setting of tumor clearance. We compared no treatment control mice vs mice treated with mock-transduced or IL-15/DNR-transduced NK cell products. Elevated levels of IL-15 were detected in the plasma of mice treated with IL-15/DNR-transduced NK cells. These elevated IL-15 levels corresponded with NK cell persistence in the brain measured by ddPCR. However, no other cytokines were upregulated. CONCLUSIONS We observed improved tumor clearance when NK cells were both protected against immune suppressive TGF-β and were capable of secreting the stimulatory cytokine IL15. We are currently performing additional experiments to determine whether toxicity from IL15 secretion occurs. To potentially mitigate this toxicity we plan to engineer a suicide gene into these constructs.
OTHR-11. THE IMPORTANCE AND INFLUENCE OF PATIENT FAMILY INVOLVEMENT IN PEDIATRIC NEURO-ONCOLOGY RESEARCH
Authors: Nicole Lyons, Adam Resnick, Angela Waanders, Javad Nazarian, Miriam Bornhorst, Jane E Minturn, Mateusz Koptyra, Michelle Monje-Deisseroth, Mark Souweidane, Jeffery P Greenfield, Amy Smith, Julia Hegert, Ginny McLean, Patti Gustafson, Allen Gustafson, Lisa Ward
Journal: Neuro-Oncology (2023)

Abstract The involvement of patient families in clinical research in pediatric brain cancer is an underutilized tool that benefits all those involved. These families are ultimately responsible for making decisions on treatment, as well as end-of-life decisions such as post-mortem tissue donation. As demonstrated by organizations such as Gift from a Child, listening to family input on how to best have the conversation surrounding post-mortem tissue donation has led to an increase in total donations, as well as parents stating they are overwhelmingly happy with their decision to donate. Tissue donation is just one example of a large, complex hindrance in the field that had not previously been addressed successfully. Due to the rarity and devastating impact of pediatric brain tumors, the family community is tight-knit and passionate. There is incredibly impactful communication that happens between families influencing decision-making for treatment, funding, and advocacy. Partnering with families allows care teams and researchers both the ability to understand the decision-making process as well as educate and discuss with the families. Surveys of families overwhelmingly show satisfaction with the decision to donate post-mortem and dissatisfaction when they are deprived of the option. Frustration with the lack of treatment has led families to become more proactive in both their child’s treatment and future research. Increasingly, family advocates are becoming more sophisticated in their support of research opportunities. An example of this spearheading the creation of an open access, safe, anonymized data bank with clinical data paired to the patient’s tumor tissue. Family foundations are actively partnering with researchers and industry to make it happen. It is clear that this type of partnership is a strong force for change that benefits researchers, clinicians, and most importantly, patients and their families.
METB-08. GENOMIC AND MOLECULAR PROFILING OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS: A SINGLE INSTITUTION ANALYSIS
Authors: Cassie Kline, Fumin Lin, Angela Liou, Adam Kraya, Kristina Cole, Michael Fisher, Marilyn Li
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Molecular characterization has revolutionized management of pediatric central nervous system (CNS) tumors, with genomic sequencing for diagnosis and determination of actionable variants now largely considered standard of care. We report a single institution’s experience performing genomic sequencing for pediatric CNS tumors over nearly five years. METHODS Nucleic acid isolated from tumor tissue and paired normal specimens from patients at Children’s Hospital of Philadelphia (CHOP) undergoes paired next generation sequencing (NGS) and copy number analyses of 237 cancer genes and a fusion panel of more than 700 exons of 117 cancer genes (tumor only). All variants are tiered 1-4 according to known clinical significance. Descriptive statistics summarize clinical and molecular data and ensemble-based methods will be used to correlate molecular and clinical characteristics. RESULTS Between January 1, 2016 and June 30, 2020, 497 patients ≤ 21 years old with median age of 9.5 years (n=243 females; 49%) contributed to 539 cases across 25 CNS tumor subtypes. The most common diagnoses were pilocytic astrocytoma (n=118), medulloblastoma (n=49), and diffuse midline glioma (DMG; n=39). Clinically significant variants (tier 1,2) were detected in 91% of the patients. Most tumors demonstrated tier 1,2 single nucleotide variants (SNV)/insertions/deletions (n=263, 53%), most commonly in TP53&amp;gt;BRAF&amp;gt;H3F3A, and/or CNVs (n=310, 62%), most commonly gains of 7q&amp;gt;7p&amp;gt;1q. Thirty percent of tumors demonstrated tier 1,2 fusions (n=149), most commonly involving BRAF, NTRK2, or FGFR. Average tumor mutation burden in patients without germline predispositions was 3.5/Mbp (standard deviation 3.8). Germline/presumed germline pathogenic variants were found in 18% (90/497) of patients tested with most common germline alterations in TP53 followed by NF1 and APC. CONCLUSION A large, single site cohort of molecularly characterized CNS tumors demonstrate the clinical and biologic utility of real-time, institution-based genomic sequencing. Molecular findings in correlation with clinical characteristics and outcomes are underway.
HGG-10. A SAFETY AND EFFICACY STUDY OF NOVOTTF-100A FOR PEDIATRIC HIGH-GRADE GLIOMA: RESULTS OF THE PLANNED INTERIM ANALYSIS OF THE FIRST THREE CASES
Authors: Atsushi Makimoto, Keita Terashima, Ryo Nishikawa, Hiroyuki Fujisaki, Jun Kurihara, Satoshi Ihara, Jun-ichi Adachi, Mikako Enokizono, Yoshihiko Morikawa, Yuki Yuza
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The safety and efficacy of Tumor-Treating Fields (TTFields) therapy for pediatric diffuse high-grade glioma (HGG) are uncertain. Despite differences between adult GBM and pediatric HGG in terms of genetic etiology, both have certain clinical behaviors in common, allowing TTFields therapy to be tested in pediatric HGG. METHODS The present study [jRCTs032200423] aims to evaluate the safety of NovoTTF-100A in pediatric HGG and conduct an exploratory analysis of its efficacy. The target population is ten children aged 5 to 17 years with newly diagnosed supratentorial HGG or its first-recurrence following frontline therapy. After completion of surgical resection of the tumor and radiation therapy, all the patients will receive TTFields therapy using NovoTTF-100A for 28 days per course for up to 26 courses until the end-of-therapy criteria (including disease progression) are met. The primary endpoint is the adverse event rate with causality. The secondary endpoints include various efficacy parameters and quality of life. In total, the ten patients will be enrolled by September 2023. RESULTS The planned interim analysis, which was done in October 2022, included 3 female patients aged 14, 17, and 9 years, respectively. All had a histological grade 4 tumor, two of which were radiation-induced secondary HGG. Although the first patient with recurrent disease had early progression after enrollment and experienced disease-related adverse events, no serious, treatment-related toxicities or device-related issues were observed. The second patient had a recurrence after six courses, and the third patient remained through the second course. All 3 patients were able to maintain device usage of 75% or more of the time, in alignment with use recommendations, suggesting treatment feasibility. DISCUSSION Based on the results presented above, the study was resumed as the current, multicentric study aimed at obtaining approval for the expanded use of NovoTTF-100A for pediatric HGG.
IMMU-21. ELUCIDATING THE CELLULAR MECHANISMS OF THERAPEUTIC BENEFIT UNDERLYING ADOPTIVE CELLULAR THERAPY IN MODELS OF GLIOMA
Authors: John Figg, Connor Francis, Dan Jin, Bayli DiVita Dean, Alexandra Reid, David Hilferty, Brianna McDonald, Catherine Flores, Duane Mitchell
Journal: Neuro-Oncology (2023)

Abstract Among pediatric cancers, malignancies of the brain carry significant morbidity and mortality, harboring dismal prognosis and poor outcomes. Our group has previously shown that adoptive cellular therapy (ACT) provides therapeutic benefit against central nervous system (CNS) malignancies, including medulloblastoma and high-grade glioma. In this study, we characterized cell cycling differences of immune sub-populations in peripheral lymphoid and tumor tissue compartments in vivo. ACT was conducted in orthotopic KR158 luciferase tumor-bearing mice, a syngeneic murine glioma model. Five days following intracranial implantation of tumor cells, mice were treated with ACT which included the following elements: total body irradiation, hematopoietic stem cell transplantation, one dose of tumor-activated splenocytes and three weekly doses of dendritic cells that had been electroporated with tumor-derived ribonucleic acid. One week after the completion of ACT, bromodeoxyuridine (BRDU) was administered to mice 12-hours prior to tissue collection and flow cytometry was utilized to measure the level of BRDU incorporation. 7-aminoactinomycin-D was used in conjunction with BRDU to provide insight into all phases of the cell cycle. We observed significant differences in cycling populations of myeloid derived suppressor cells (MDSC) and T-cells. In ACT-treated-mice, MDSCs found in secondary lymphoid tissues were significantly more proliferative. In the tumor microenvironment (TME), proliferating MDSCs were significantly reduced compared to mice that did not receive treatment. Frequencies of proliferating CD4+ and CD8+ T-cells were significantly increased in cervical lymph node and TME but reduced in spleen. These findings suggest that ACT alters immune cycling in peripheral lymphoid tissues and TME to potentially promote antitumor T-cell responses and minimize MDSC-mediated immunosuppression. While ACT-mediated alterations to immune cell cycling are likely a major contributor to the therapy’s benefit, it is unlikely to be the sole mechanism. Further exploration into other functional pathways, namely migration, is needed to explain changes to immune populations following ACT.